Image Credit: © Corona Borealis - stock.adobe.com
Image Credit: © Corona Borealis - stock.adobe.com
The FDA has granted orphan drug designation to bexobrutideg (NX-5948), an orally bioavailable, brain penetrant, BTK degrader, for the treatment of patients with Waldenström macroglobulinemia.1
This designation follows the agent’s fast track designation from the FDA in December 2024, for the treatment of adult patients with relapsed/refractory Waldenström macroglobulinemia who have received at least 2 lines of therapy, including a BTK inhibitor.2 Bexobrutideg is under evaluation in the ongoing phase 1a/b NX-5948-301 trial (NCT05131022) in adults with relapsed or refractory B-cell malignancies.1
“The FDA’s orphan drug designation for bexobrutideg, also known as NX-5948, represents an important milestone in our regulatory strategy and underscores the significant unmet medical need for improved treatments for Waldenström macroglobulinemia,” Arthur T. Sands, MD, PhD, president and chief executive officer of Nurix, stated in a news release. “Granting of the designation highlights bexobrutideg’s potential to provide patients with Waldenström macroglobulinemia a promising new therapeutic option. We are also pleased to announce that our investigational therapy bexobrutideg has been assigned a nonproprietary name reflecting its novel mechanism of action, designated with the unique suffix “deg” for degrader.”
The BCR signaling pathway mediated by BTK is a fundamental part of oncogenesis and a validated therapeutic target in Waldenström macroglobulinemia.3 BTK degraders, which are fundamentally different from BTK inhibitors,1 can overcome treatment-emergent BTK inhibitor resistance mutations and address BTK scaffolding function.3 Because of its mechanism, NX-5948 is designed to disrupt BCR signaling by destroying BTK protein and eliminating its immediate and downstream functions.
The ongoing phase 1a/b trial is evaluating the agent in patients with relapsed or refractory B-cell malignancies. To be eligible for enrollment patients must be at least 18 years of age, have relapsed/refractory disease, received at least 2 prior lines of therapy, and have an ECOG performance status of 0 or 1. For patients with primary central nervous system (CNS) lymphoma at least 1 prior line of therapy was required in addition to an ECOG performance status between 0 and 2.
The dose-escalation portion of the trial enrolled up to 66 patients with non-Hodgkin lymphoma/ Waldenström macroglobulinemia. In dose expansion patients in the global Waldenström macroglobulinemia cohort were in their third line of therapy, and those in the UK cohort were in their second line of therapy, both following prior exposure to BTK inhibitors.
Updated findings from the trial, which were presented at the 12th International Workshop on Waldenström Macroglobulinemia, revealed robust, rapid, and sustained BTK degradation in all patients enrolled in the trial at all dose levels assessed (50 mg, 100 mg, 200 mg, 300 mg, 450 mg, and 600 mg). By day 15, NX-5948 showed greater than 80% degradation in BTK. Moreover, a steady decrease in IgM levels were seen in patients with Waldenström macroglobulinemia treated with NX-5948.
Within the Waldenström macroglobulinemia cohort (n = 13) of disease-evaluable patients (n = 9), the objective response rate was 77.8%, consisting only of partial/marginal responses. Two patients (22.2%) also experienced stable disease.
The median age of the Waldenström macroglobulinemia cohort was 74.0 years (range, 64-82) and most patients were male (84.6%) and had an ECOG performance status of 1 (76.9%). No patients had CNS involvement. The median number of prior lines of therapy was 3.0 (range, 2-5). Prior therapies included pirtobrutinib (Jaypirca; 23.1%), BCL2 inhibitors (7.7%), BTK and BCL2 inhibitors (7.7%), and chemotherapy/chemoimmunotherapy (100%). Most patients also had mutations in MYD88 (61.5%) and CXCR4 (15.4%).
“We are excited that bexobrutideg has been recognized by the USAN Council as a unique entity and member of a new class of small molecule drugs, targeted protein degraders,” Gwenn Hansen, PhD, chief scientific officer of Nurix, stated.1 “The catalytic mechanism of action and event driven pharmacology triggering ubiquitination and proteasomal degradation of a target protein is highly differentiated from inhibitors and allows degraders to eliminate the totality of a protein’s function. In our BTK degrader clinical program, we have also established that degraders can eliminate mutant oncoproteins that have proven to be resistant to inhibitor therapy.”
Additional data from the trial are expected in 2025.
References
Nurix announces U.S. FDA orphan drug designation granted to bexobrutideg (NX-5948) for the treatment of Waldenström macroglobulinemia. News release. Nurix Therapeutics. March 17, 2025. Accessed March 18, 2025. https://ir.nurixtx.com/news-releases/news-release-details/nurix-announces-us-fda-orphan-drug-designation-granted
Nurix Therapeutics receives U.S. FDA fast track designation for NX-5948 for the treatment of relapsed or refractory Waldenstrom’s macroglobulinemia. News release. Nurix Therapeutics. December 19, 2024. Accessed March 18, 2025. https://ir.nurixtx.com/news-releases/news-release-details/nurix-therapeutics-receives-us-fda-fast-track-designation-nx-0
NX-5948: BTK degrader with activity in lymphoid malignancies. Nurix. October 19, 2024. Accessed March 18, 2025. https://www.nurixtx.com/wp-content/uploads/2025/01/2024-10-19-IWWM-Presentation.pdf